P738: EXPRESSION OF TRANSPOSABLE ELEMENTS IN CD34+ CELLS IN MYELODYSPLASTIC SYNDROMES
Authors: Z. Krejcik, A. Hrustincova, I. Trsova, D. Kundrat, K. Szikszai, M. Belickova, J. Cernak, A. Jonasova, M. Dostalova Merkerova
Journal: HemaSphere (2022)

Background: Myelodysplastic syndromes (MDS) are a heterogenous group of malignant hematopoietic stem cell (HSC) disorders characterized by genomic instability resulting in aberrant differentiation of HSCs, peripheral blood cytopenia, and a tendency toward leukemic transformation. Transposable elements (TEs) are common in the human genome and, with regard to their ability to change the position in the genome, may represent one of the sources of this instability. Although TE dysregulation has previously been reported in different hematological malignancies, e.g., in acute myeloid leukemia (AML), information about TEs in MDS is rare. In the past, Colombo et al. demonstrated suppressed TE expression in higher risk MDS in a small cohort of patients. They proposed this suppression as a mechanism for immune escape in MDS/AML because the higher TE expression can potentially trigger immune-mediated cell clearance of cancer cells via “viral mimicry” pathways. Aims: Our aims were to identify, quantify and compare TE expression in different stages of MDS on a larger cohort of patients to provide a deeper insight into their occurrence and possible roles in MDS. Methods: We prepared, sequenced, and analyzed rRNA-depleted RNA libraries of CD34+ HSCs in a cohort of 75 MDS patients, and 13 healthy controls, using the SalmonTE tool for the TE detection. Results: Comparison between healthy controls and MDS patients revealed significantly upregulated class I LTR (Long Terminal Repeat) retrotransposons (p = 0.0006, logFC = 0.040), especially then ERV1 (Endogenous Retrovirus) class (p = 0.0002, logFC = 0.052), in MDS patients. Detailed analysis revealed 11 significantly (FDR < 0.05) differentially expressed TEs, nine upregulated (ERV1: HERV-Fc1, MER51E, LTR27E, MER65C, HUERS-P1, PABL_A, ERV3: MER54B, CR1: X5A_LINE, SINE (Short Interspersed Element): MIR3) and only two downregulated (ERV1: LTR71A, LTR26E) in the group of MDS patients. After stratification of patients into lower (IPSS-R score ≤ 3.5, n = 48) and higher risk (IPSS-R score ≥ 4, n = 27) categories, we observed significant dysregulation of non-LTR retrotransposons in general, and in particular of SINE (p = 6.2x10-14, logFC = -0.21) and LINE1 (Long Interspersed Element) (p = 3x10-7, logFC = 0.06) clades. Detailed differential expression analysis revealed that 18 out of 21 most significantly (FDR < 0.001) deregulated TEs were suppressed in higher risk MDS, namely AluY, AluYb8, AluYd8, AluYe2, AluSq4, AluYa1, AluYa5, AluYb3a2, AluYc1, AluYbc3a, AluYe5, AluYf2, SVA_B and SVA_F (all SINE), L1HS (LINE1), LTR12E and LTR1A2 (both ERV1); and only three TEs were upregulated (HARLEQUIN, LTR24C, PABL_AI (all ERV1)). Summary/Conclusion: To our knowledge, this is the first report on TE expression and MDS-risk specific dysregulation in a larger cohort of MDS patients, revealing their importance in the pathogenesis of MDS. Significant suppression of TEs observed in higher risk MDS patients supports the previously formulated potential mechanism of immune escape in these MDS patients. Acknowledgements: Supported by AZV CR (NU20-03-00412) and MH CZ-DRO (UHKT 00023736). Reference: Colombo et al. Suppression of transposable elements in leukemic stem cells. Sci Rep. 2017. 1;7(1):7029. doi: 10.1038/s41598-017-07356-9.